DEVELOPMENT OF DIGESTIVE SYSTEM

Meidona N. Milla Anatomy Department Faculty of Medicine Sultan Agung Islamic University

LEARNING OBJECTIVES

• Origin of GI Tract • Formation of Primitive Gut • Mesentery development • Foregut development • Midgut development • Hindgut development

ORIGIN OF DIGESTIVE SYSTEM

• Epithel lining the GI tract ( digestive system) and parenchyma of the glands derived from endoderm • Muscle, connective tissue, and peritoneal components of the wall of the gut are derived from splanchnic mesoderm • The development of specific organs depend of the reciprocal interaction between endoderm and splanchnic mesoderm. The expression of morphogen Sonic hedgehog (SHH) in endoderm will induce the HOX code in mesoderm encode mesoderm types of structure that will form.

Molecular basic of GIT formation

The morphogen sonic hedgehog (SHH) is secreted by gut endoderm and induces a nested expression of HOX genes in surrounding mesoderm. HOX expression then initiates a cascade of genes that “instruct” gut endoderm to differentiate into its regional identities. Signaling between the two tissues is an example of an epithelial-mesenchymal interaction Embryonic Folding Various stages of embryo development ( transverse section) FORMATION OF PRIMITIVE GUT

• Cephalocaudal and lateral folding of embryo  formation of blind end tube from cephalic until caudal portion of embryo  Primitive Gut • 4 sections of primitive gut: 1. Pharyngeal gut 2. Foregut 3. Midgut 4. Hindgut

Endoderm Development of GIT MESENTERY

• Is double layered peritoneum that cover some particular organs and connect them to the body wall • Gut tubes and their derivation are fixed to ventral and dorsal body wall by mesentery • Organs that are fully covered by mesentery  intraperitoneal organs • Organs that are directly attached in posterior body wall and covered by mesentery only on their anterior part  retroperitoneal organs

Dorsal mesentery • passes from distal part of esophagus to cloacal region. • When it passes :  the stomach  dorsal mesogastrium or major omentum  Duodenum  dorsal mesoduodenum  Jejenum ileum  mesenterium propius  Colon  dorsal mesocolon

Ventral Mesentery • In terminal part of esophagus, stomach and proximal part of duodenum • derived from transversal septum • Liver bud growth in transversal septum will divide the ventral mesentery into 2 parts  lesser omentum and falciform ligament Primitive Mesentery FOREGUT DEVELOPMENT

• Lies from pharyngeal tube until liver bud • Organs: esophagus, trachea, lung bud, stomach, upper part of duodenum, liver and biliary ducts, pancreas, spleen

FOREGUT DEVELOPMENT 1. ESOPHAGUS • 4TH WEEK  respiratory diverticulum appears in ventral wall of foregut, right after pharyngeal gut  slowly separated from foregut by esophageal septum

• Clinical Correlation  Esophageal Atresia / Fistula due to esophageal septum deviation, etc  Stenosis Esophagus ( usually 1/3 distal part)  incomplete recanalization, abnormal bloodflow, etc  Hernia hiatus congenital  esophagus fails to lengthen, stomach is pulled upward Esophageal atresia / fistula FOREGUT DEVELOPMENT

2. STOMACH ( GASTER / VENTRICULUS)  4 WEEKS : due to different growth speed of each part of its wall and the development of surrounding organs  stomach change in its shape and positon

STOMACH ROTATION in longitudinal axis  change position of dorsal and ventral mesentery  formation of bursa omentalis  in anteroposterior axis  dorsal mesogastrium protruded distally, covering transverse colon and gut loop ( Like an apron) slowly difuses, 2 layers becomes 1 Stomach rotation Mesogastrium change in position durung stomach rotation

FOREGUT DEVELOPMENT

CLINICAL CORRELATION Pyloruc Stenosis  longitudinal muscle hypertrophy and slow growing of circular muscle SPLEEN • Spleen bud appears in dorsal mesentery  change position due to stomach rotation • connected with kidney  renolienalis ligament • Connected with stomach gastrolienalis ligament

PANCREAS • The pancreas is formed by two buds originating from the endodermal lining of the duodenum  dorsal bud ( from dorsal mesentery) and ventral bud • When the duodenum rotates to the right and becomes C-shaped  the ventral pancreatic bud moves dorsally in a manner similar to the shifting of the entrance of the bile duct  ventral bud comes to lie immediately below and behind the dorsal bud • The ventral bud forms: the uncinate process and inferior part of the head of the pancreas. • The remaining part of the gland is derived from the dorsal bud.

Pancreas Formation Clinical Correlation • Annular Pancreas THE LENGTHEN AND DIFUSION OF DORSAL MESOGASTRIUM TO THE DORSAL BODY WALL  CAUSE PANCREAS THAT IS PREVIOUSLY LOCATED IN DORSAL MESOGASTRIUM REACH ITS FINAL POSITION IN POSTERIOR BODY WALL, COVERED BY PERITONEUM ONLY ON ITS ANTERIOR PART  SECONDARY RETROPERITONEAL

FOREGUT DERIVATION

LIVER and BILLIARY DUCTS • Transverse Septum : mesoderm pate between pericardium cavity and yolk stalk • Liver bud grows into the transverse septum, will split the ventral mesentery into:  liver peritoneum  Falciform ligament ( inside: umbilical vein  degenerated  lig. Rotundum / lig. Teres hepatis)  Omentum minus  connects liver and duodenum  hepatoduodenalis ligament (inside: portal triad ) • Liver bud grows into transverse septum  connection between liver and duodenum is narrowed  becomes billiary ducts • Small buds grow in the connection tissue  vesical fellea and cystic duct

Liver Bud Growth FOREGUT DEVELOPMENT

• Hepatic cord epitel entangled around vitelline vein  umbilical vein  hepar sinusoid • Hepatic cords differentiate into parenchyme tissues and tissues that will cover biliary ducts • Hemopoetic and Kupffer, stroma  derived from mesoderm tissues in transverse septum • 10th week : liver weight 10% from total body weight  hemopoetic function • 12th week: bile salt production MOLECULAR INDUCTION OF LIVER GROWTH

• All of the foregut endoderm has the potential to express liver-specific genes and to differentiate into liver tissue. • However, this expression is blocked by factors produced by surrounding tissues, including ectoderm, non-cardiac mesoderm, and particularly the notochord • The action of these inhibitors is blocked in the prospective hepatic region by fibroblast growth factors (FGFs) secreted by cardiac mesoderm. • The cardiac mesoderm “instructs” gut endoderm to express liver specific genes by inhibiting an inhibitory factor of these same genes  cells in the liver field differentiate into both hepatocytes and biliary cell lineages, • a process that is at least partially regulated by hepatocyte nuclear transcription factors (HNF3 and 4). FOREGUT DEVELOPMENT

• Clinical case  atresia of extrahepatic biliary ducts

FOREGUT DEVELOPMENT

DUODENUM • Derived from caudal part of foregut and cranial part of midgut • Due to stomach rotation  duodenum becomes C-shaped and rotates to the right direction ( along with caput pancreas growth)  duodenum turns from its center position to the left portion of abdomen  duodenum and pancreas are pressed to the dorsal body wall  secondary retroperitoneal • Duodenum vascularization: branches of celiac trunk and superior mesentery artery

MIDGUT DEVELOPMENT

• Start from distal part of biliary ducts until 2/3 proximal transverse colon • Fast growing gut and its mesentery  gut loop • Cranial part  still connected with yolk sac through vitelline duct • Cranial part of midgut derives : duodenum ( distal part),cranial part of jejenum • Caudal part of midgut derives: ileum distal, coecum, appendix, ascending colon and 2/3 transverse colon MIDGUT DERIVATION PHYSIOLOGIC HERNIA • 6th week: Primary gut loop grows fast especially in cranial part  loops enter the extraembryonic coelom in umbilical cord ( temporarily) • 10th week gut loops back into the abdominal cavity

MIDGUT DERIVATION MIDGUT ROTATION • Axis of Rotation superior mesentery artery • 270° counter clockwise: 90°  During herniation • 180°  in the abdomen • 10th week: herniated gut back into abdomen • Jejenum comes in first, follows by other parts of the loops and finally part comes in is coecum • Coecum firsty located in right upper quadrant  rotate caudally  right lower quadrant • During coecum rotation, distal end of coecum forms a amall diverticle -> primitive appendix

MIDGUT DERIVATION

GUT MESENTERY • Change position due to gut rotation • In ascending and descending part of colon, mesentery are pressed to the posterior body wall  becomes retroperitoneal organs • Intraperitoneal organs  transverse colon, coecum, appendix Mesentery attachment to the posterior body wall MIDGUT DERIVATION • CLINICAL Correlation OMPHALOCELE: herniation of abdominal viscera through an enlarged umbilical ring. The viscera, which may include liver, small and large intestines, stomach, spleen, or gallbladder, are covered by amnion GASTROSCHISIS Herniation of abdominal contents through the body wall directly into the amniotic cavity. It occurs lateral to the umbilicus usually on the right, through a region weakened by regression of the right umbilical vein, which normally disappears

MIDGUT DEVELOPMENT

MECKEL DIVERTICLE VITELINE CYST VITELINE FISTULE

• Gut Rotation Defects Abnormal rotation of the intestinal loop may result in twisting of the intestine (volvulus) and a compromise of the blood supply Reversed rotation of the intestinal loop occurs when the primary loop rotates 90◦ clockwise

Duplications of intestinal loops and cysts HINDGUT DEVELOPMENT

• Give rises to : 2/3 transverse colon, descending colon, sigmoid colon and upper part canal anal • The terminal portion of the hindgut enters into the posterior region of the cloaca, the primitive anorectal canal; • the allantois enters into the anterior portion, the primitive urogenital sinus • cloaca itself is an endoderm-lined cavity covered at its ventral boundary by surface ectoderm. This boundary between the endoderm and the ectoderm forms the cloacal membrane HINDGUT DERIVATION

• A layer of mesoderm,the urorectal septum, separates the region between the allantois and hindgut • 7th week: , the cloacal membrane ruptures, creating the anal opening for the hindgut and a ventral opening for the urogenital sinus • the caudal part of the anal canal originates in the ectoderm, and it is supplied by the inferior rectal arteries, branches of the internal pudendal arteries • The cranial part of the anal canal originates in the endoderm and is supplied by the superior rectal artery, a continuation of the inferior mesenteric artery • The junction between the endodermal and ectodermal regions of the anal canal is delineated by the pectinate line HINDGUT DERIVATION

• Rectoanal atresias, and fistulas, abnormalities in formation of the cloaca, due to ectopic positioning of the anal opening • imperforate anus, no anal opening lack of recanalization of the lower portion of the anal canal • Congenital megacolon is due to an absence of parasympathetic ganglia in the bowel wall (aganglionic megacolon or Hirschsprung disease)  Mutations in the RET gene, a tyrosine kinase receptor involved in crest cell migration

Urorectal fistula GIT Development and Vascularization SUMMARY

• The epithelium of the digestive system and the parenchyma of its derivatives originate in the endoderm; • connective tissue, muscular components, and peritoneal components originate in the mesoderm • The gut system extends from the buccopharyngeal membrane to the cloacal membrane divided into the pharyngeal gut, foregut, midgut, and hindgut • The foregut gives rise to the esophagus, the trachea and lung buds, the stomach, and the duodenum proximal to the entrance of the bile duct • liver, pancreas, and biliary apparatus develop as outgrowths of the endodermal epithelium of the upper part of the duodenum SUMMARY

• The midgut forms the primary intestinal loop gives rise to the duodenum distal to the entrance of the bile duct, and continues to the junction of the proximal two-thirds of the transverse colon • The hindgut gives rise to the region from the distal third of the transverse colon to the upper part of the anal canal; the distal part of the anal canal originates from ectoderm END OF TODAY’S LECTURE,

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